(FINANCIAL TIMES) - As global vaccination campaigns race to stay ahead of new Covid-19 variants, pioneering scientists have set out to ease fears of another pandemic by developing a single shot to protect against coronaviruses past, present and future.
Dr Melanie Saville, director of vaccine research and development at the Coalition for Epidemic Preparedness Innovations, is among those leading the charge, having issued a call for the creation of a vaccine that would be broadly protective against all betacoronaviruses and potentially any new strain "that might hop from animals to humans in the future".
"The strategy moving forward is around two key questions," she told the Financial Times. "What do we need to do to end this pandemic and then what do we need to do to prevent the next pandemic?"
Sars-Cov-2, which has killed almost 4 million people in the past 18 months, is at least the third so-called betacoronavirus that has spread among humans in the past 20 years. The family of viruses, common in bats and rodents, also includes Sars-Cov-1, which killed more than 700 people in 2003, mainly in China and Hong Kong; and Mers-Cov, which was first identified in Saudi Arabia and has resulted in more than 850 deaths since 2012.
Given that Covid-19 is unlikely to be the last coronavirus to infect humans, the development of a jab capable of protecting against all such diseases has become a central focus for some scientists.
And as Covid-19 has continued to mutate faster than originally expected - most recently with the rapid spread of the Delta variant, first identified in India - interest in their work has increased.
Within five years, "polyvalent vaccines" that protect against different varieties of coronaviruses "will hold the line to a very large degree against even new variants", Professor Chris Whitty, England's chief medical officer, told UK healthcare staff this month.
But the road to a so-called polyvalent or multivalent vaccine is fraught with challenges. Researchers have spent decades unsuccessfully seeking a vaccine for HIV - a disease that frequently throws up new strains - and the flu jab still needs to be updated annually.
Different target - epitopes
The current crop of Covid-19 vaccines, many of which have proved highly effective against the original Sars-Cov-2 strain and its subsequent variants, have focused on generating antibodies to neutralise the spike protein the virus uses to enter human cells. The difficulty with that approach, Dr Saville explained, can be that "the virus evolves to evade that immune response so... you need to constantly update your vaccine".
Multivalent vaccines, in contrast, often target pieces of protein in the virus that stimulate the immune system, known as epitopes, and specifically attack those epitopes in parts of the virus that do not mutate, even under "evolutionary pressure", according to Dr Saville.
Many such shots also seek to stimulate the production - in addition to antibodies - of T-cells, which, it has gradually emerged, are a crucial part of the immune response to Covid-19.
Mr Paul Higham, chief executive of Valo Therapeutics, said that by targeting epitopes with "very, very low" mutation rates, its multivalent vaccine had been able to generate a T-cell response that could work for Covid-19, Sars, Mers and "future coronaviruses". He hoped the Helsinki and Oxford-based company would have the vaccine ready for clinical trials by the end of the year, adding that it could be available for public use "by some time in 2022".
But developing vaccines capable of fighting multiple pathogens is extremely hard. "The further apart the viruses are in terms of their composition, in terms of their sequence, the harder it is to find antibodies that will act against (them)," said Dr Dennis Burton of the Scripps Research Institute in California, who has spent many years chasing a vaccine for HIV. "For example, Sars-1 and Sars-2 are quite similar and we find lots of antibodies that will act against both viruses."
But to expand a shot to also target Mers, let alone future, more diverse coronaviruses, was far more difficult, he added.
With help from AI
Dr Saville believes that finding the epitopes able to give protection against diverse coronaviruses will require the use of artificial intelligence - something that is increasingly deployed in drug discovery to accelerate research and development.
Dr John Lewis, chief executive at Entos Pharmaceuticals, said his company had taken "a machine learning approach" for its multivalent vaccine. It partnered with a specialist AI company with software that allowed it to identify "34 different epitopes from different coronavirus proteins" that would produce the most potent human T-cell response.
"We're using pieces of the proteins that are over 90 per cent similar between Sars-1 and Sars-2 and are also found in other kinds of coronavirus where they seem to confer broad immunity," he said. "They may not provide complete protection but they should provide partial protection against many different varieties."
Entos, based in Edmonton, Canada, hopes to begin human trials within the next two months.
OSE Immunotherapeutics, a French biotech company, has used an AI algorithm that it previously deployed in developing a cancer vaccine. The technology allowed it to identify 12 epitopes targeting 11 proteins, most of them within the virus, rather than on its surface.
"As they're within the virus, they do not mutate or they mutate very little", said the firm's chief executive Alexis Peyroles, adding that the same kind of proteins could be found in both Sars-1 and Mers.
Phase 1 human trials of the jab have begun with results expected in September. OSE is already "loosely planning" phase 2, helped by financial support from the French innovation bank, BPI France, and a possible phase 3 trial in 2022.
Mr Peyroles said the vaccine might be particularly effective for people with suppressed immune systems who did not produce protective antibodies in response to the currently available vaccines. But its wider use would be as a pan-coronavirus booster for everyone, easily adapted to take account of new forms of the disease as they emerged.
"You would have a base that would remain and then add or remove new epitopes based on the new coronavirus," he said.
Broad spectrum approach
VBI Vaccines, based in Cambridge, Massachusetts, has taken a different approach. Like the current crop of Covid-19 vaccines, VBI's jab targets the spike protein but has been able to generate a broader immune response.
"When we immunised animals, we made antibodies that could protect against Covid-19, Sars and Mers - that's like making antibodies that can see red, yellow and blue," said the firm's chief scientific officer David Anderson.
"But the immune system is very flexible and you can teach it to see something that's a little bit between the red and the yellow, or the yellow and the blue, 'spike proteins'. So now, they're seeing a shade of orange or green, which shows that you've essentially broadened the immune response," he added. "The idea is that these antibodies may now go after variants that will continue to mutate and emerge over time."
There is no precedent for the company's "broad spectrum approach", but Dr Anderson is optimistic. The shot has received financial backing from both CEPI and the Canadian government with human trials expected to start in the second half of this year.
VBI's chief executive Jeff Baxter said it could be with the regulators for consideration in 12 to 14 months. "Science doesn't always go as you expect and it constantly evolves as we learn more," he said. "But it's very exciting to think that maybe in two years' time, everyone could be getting a booster of a multivalent pan-coronavirus vaccine."